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JP-2026075626-A - Novel GLP-1 analog

JP2026075626AJP 2026075626 AJP2026075626 AJP 2026075626AJP-2026075626-A

Abstract

[Problem] To provide a GLP-1 analog that has optimally desirable properties in terms of stability and duration of action. [Solution] This disclosure relates to a novel glucagon-like peptide-1 (GLP-1) (7-37) analog having an amino acid sequence with Leu or Ile at the C-terminus. This novel analog is a potent GLP-1 agonist with reduced adverse effects and improved duration of action. This disclosure further relates to a novel acylated derivative of the analog that has further improved potency and duration of action and is suitable for oral administration. The analog of this disclosure may be useful in the treatment of diabetes and obesity. [Selection Diagram] None

Inventors

  • テナッティ，ラジャマンナル
  • ジョシー，ディレン・ラメシュチャンドラ
  • ソニー，クルナル・ハリシュバイ
  • ティワーリー，アビシェーク
  • パテル，ヴィプルクマール・シャンカルバイ
  • チャトゥルヴェーディー，ニシス
  • ブラーデ，ヴィノード・サンパトラオ
  • シャヒ，プラディープ・ディネシュ
  • ナタラジャン，ムツクマラン
  • ナガラジャ，ラビシャンカラ・マダバティ
  • ザラワディア，リシ・マンスクラル
  • パンディア，クナル
  • パテル，ブリエッシュクマール

Assignees

  • サン ファーマシューティカル インダストリーズ リミテッド

Dates

Publication Date
20260508
Application Date
20260130
Priority Date
20180405

Claims (10)

  1. A polypeptide comprising the following amino acid sequence, H-X2-X3-X4-G-TFT-S-DV-S-SY-L-X16-G- Q-A-A-X21-E-F-X24-A-W-L-V-R-G-R-G-X33-X3 4 In the formula, X2 is Ser, Ser(OMe), D-Ser, D-Ser(OMe), Ala , or Aib, X3 does not exist, or it is Gln. X4 is Glu, X16 is Glu, X24 is Ile, X33 is Leu, -D-Leu, D-Ile, or Ile, X34 does not exist. X21 is Lys, and the amino (ε-amino) group in the side chain of Lys is acylated at the following point: In the formula, Q and T are absent. U is either absent, or -C(O) -CH2 -O-( CH2 ) 2 -O-( CH2 ) 2 } is -NH-, where } is the attachment point with the base W, Either W is absent, or -C(O) -CH2 -O-( CH2 ) 2 -O-( CH2 ) 2 -NH-], -C(O)-NH-(CH 2 ) 3-4 -NH-], -C(O)-C(CH 3 ) 2 -NH-], and A selection is made from the group consisting of, where in the formula, ] is the attachment point with base Y, Y is -C(O)-( CH2 ) 2 -CH(COOH)NH--, and -- is the attachment point with group Z. A polypeptide in which Z is -C(O)-( CH2 ) n -COOH or -C(O)-( CH2 ) n - CH3 , where n is an integer between 14 and 20.
  2. X2 is Aib, X3 does not exist, X33 is Leu, U is -C(O) -CH2 -O-( CH2 ) 2 -O-( CH2 ) 2 -NH-, W is -C(O) -CH2 -O-( CH2 ) 2 -O-( CH2 ) 2 -NH-, The polypeptide according to claim 1, wherein Z is -C(O)-( CH2 ) n -COOH, where n is an integer 16.
  3. X2 is Aib, X3 does not exist, X33 is Leu, U is -C(O) -CH2 -O-( CH2 ) 2 -O-( CH2 ) 2 -NH-, W is -C(O)-C( CH3 ) 2 -NH-, The polypeptide according to claim 1, wherein Z is -C(O)-( CH2 ) n -COOH, where n is an integer 16.
  4. X2 is Aib, X3 does not exist. X33 is Leu, U is -C(O) -CH2 -O-( CH2 ) 2 -O-( CH2 ) 2 -NH-, W is -C(O)-NH-( CH2 ) 4 -NH-, The polypeptide according to claim 1, wherein Z is -C(O)-( CH2 ) n -COOH, where n is an integer 16.
  5. X2 is Aib, X3 does not exist, X33 is Leu, U is -C(O) -CH2 -O-( CH2 ) 2 -O-( CH2 ) 2 -NH-, W And, The polypeptide according to claim 1, wherein Z is -C(O)-( CH2 ) n -COOH, where n is an integer 16.
  6. X2 is Aib, X3 does not exist, X33 is Leu, U is -C(O) -CH2 -O-( CH2 ) 2 -O-( CH2 ) 2 -NH-, W is -C(O)-NH-( CH2 ) 3 -NH-, The polypeptide according to claim 1, wherein Z is -C(O)-( CH2 ) n -COOH, where n is an integer 16.
  7. X2 is Ser, Ser(OMe), D-Ser, D-Ser(OMe), X3 does not exist. X33 is Leu, U is -C(O) -CH2 -O-( CH2 ) 2 -O-( CH2 ) 2 -NH-, W is -C(O)-CH 2 -O-(CH 2 ) 2 -O-(CH 2 ) 2 -NH-], -C(O )-NH-( CH2 ) 3-4 -NH-], -C(O)-C( CH3 ) 2- NH-], The polypeptide according to claim 1, wherein Z is -C(O)-( CH2 ) n -COOH or -C(O)-( CH2 ) n - CH3 , where n is an integer from 14 to 20.
  8. W is -C(O)-NH-(CH 2 ) 3-4 -NH-], -C(O)-C(CH 3 ) 2 A polypeptide according to claim 1, selected from the group consisting of -NH- and the following formulas.
  9. X2 is Ala, X3 does not exist. X33 is Leu, W does not exist, Claim 1, where Z is -C(O)-( CH2 ) n - CH3 , and n is an integer 14. Polypeptides as described.
  10. X2 is Aib, X3 does not exist, X33 is Leu, W does not exist, Claim 1, where Z is -C(O)-( CH2 ) n - CH3 , and n is an integer 14. Polypeptides as described.

Description

Cross-reference of related applications This application is application number IN2018/21013109 (filed April 5, 2018), I N2018/21040468 (filed October 26, 2018), and IN2018/ This asserts the interests of three Indian provisional applications, including 21040474 (filed October 26, 2018), which are incorporated herein by reference. This disclosure relates to a novel glucagon-like peptide-1 (GLP-1) (7-38) analog having an amino acid sequence with Leu or Ile at the C-terminus. This novel analog is a potent GLP-1 agonist with reduced adverse effects and improved duration of action. This disclosure further relates to a novel acylated derivative of the analog that has further improved potency and duration of action and is suitable for oral administration. The analog disclosed herein is acylated at the extension portion, which increases the duration of activity of the compound. The analog disclosed herein may be useful in the treatment of diabetes and obesity. Glucagon-like peptide-1 (GLP-1) is a hormone primarily produced in enteroendocrine L cells of the intestine and secreted into the bloodstream when food containing fats, protein hydrolysates, and/or glucose enters the duodenum. GLP-1 is derived from cell-specific post-translational processing of the preproglucagon gene. Initially, peptide GLP-1(1-37) was identified from this processing, but it was found to recognize pancreatic receptors and two N-terminal cleavage products, GLP-1(7-37), were determined to be active species in vivo. These were (SEQ ID NO: 1) and GLP-1(7-36) amide. GLP-1 has been found to stimulate insulin secretion, thereby causing glucose uptake by cells and a decrease in serum blood glucose levels. GLP-1 agonists are available as preferred drugs for the treatment of type 2 diabetes (T2DM) because they do not cause hypoglycemia and have a good benefit of weight loss. The endogenous substances GLP-1(7-37) and GLP-1(7-36) amide are cleaved by peptidases and therefore have a very short half-life. Efforts have been made to improve performance by developing GLP-1 analogs with improved half-lives. The first drug approved in 2005 was exenatide, administered at a dose level of 10 mcg twice daily, which was found to show a significant improvement in HbA1c, a glucose control marker. Furthermore, Novo Nordisk is administered as liraglutide, 1.8 mg once daily by subcutaneous injection. They developed U.S. Patent No. 6,268,343 (Sequence ID 2), which was approved in 2010. Further research and development will lead to the development of albiglutide (Albig) by GSK. Dulaglutide (Dul), developed by Eli Lilly Products administered once a week, such as aglutide, have been manufactured. More recently, GLP- 1. An analog: semaglutide (International Publication WO2006/09) Semaglutide (SEQ ID NO: 7537(A2)) was approved by the USFDA. It is marketed under the brand name Ozempic®. It is administered once a week by subcutaneous injection. Numerous attempts to create GLP-1 analogs with improved potency and duration of action have been reported in the literature. (U.S. Patent No. 7,291,594(B2)) The present invention discloses GLP-1(7-35) derivatives that provide high bioavailability via mucosa by adding several residues of arginine and/or lysine to their C-terminus. The US '594 patent further discloses that these derivatives can confer resistance to dipeptidyl peptidase IV (DPP-IV) by substituting amino acid 8 with Ser in their GLP-1 amino acid sequence, or to trypsin by substituting amino acids 26 and 34 with Glun and Asn, respectively. U.S. Patent No. 7,893,017 (B2) (U.S. 017 patent) discloses an acylated GLP-1 analog in which the GLP-1 analog is stable to DPP-IV by modifying GLP-1 (7-37) with at least one amino acid residue at positions 7 and 8, wherein the acylation is a diacid directly attached to the C-terminal amino acid residue of the GLP-1 analog. U.S. Patent No. 8,951,959 (B2) (US'959 patent) describes a DPP-IV resistant GL having a non-proteogenic amino acid residue containing a trifluoromethyl group at position 8 relative to the sequence GLP-1, and acylated with a moiety containing two acidic groups at the lysine residue at position 26. P-1 (7-37) analogues are disclosed. U.S. Patent No. 7,084,243(B2) (US'243 patent) discloses a GLP-1(7-37) analog as a DPP-IV resistant peptide, having Val or Gly at position 8 relative to the sequence GLP-1(7-37). International publication no. WO2017/149070(A1) (WO'070) is GLP-1 ( We disclose GLP-1 analogs having a Trp at the position corresponding to position 8 (7-37), and these Trp8 compounds have been shown to be very stable against degradation by DPP-IV. International publication no. WO2004/103390 (A2) (WO'390) is at position P' 1 ( It is disclosed that modification at position 9 (corresponding to position 9 in the case of GLP-1(7-37)) can produce a GLP-1 analog that significantly reduces the sensitivity to enzyme-mediated cleavage (e.g., DPP-IV) of the natural substrate, while still maintaining the biological activity of the